Genetic predictors of response to treatment with crhr1 antagonists

Abstract

The invention relates inter alia to methods for predicting the response of patients with depressive symptoms and/or anxiety symptoms to treatment with a CRHR1 antagonist, and algorithms, kits, microarrays, probes and or/primers for use in such methods.

1 . A method for providing an algorithm for predicting a treatment response to CRHR1 antagonists in patients with depressive symptoms and/or anxiety symptoms, wherein the method comprises the following steps:
 (a) performing a single nucleotide polymorphism (SNP) genotyping analysis in a group of patients with depressive symptoms and/or anxiety symptoms;   (b) determining a value indicative for CRH activity in each patient of the group, wherein a value indicative for CRH overactivity is indicative for a patient responding to a treatment with a CRHR1 antagonist;   (c) identifying at least one SNP associated with a value indicative for CRH overactivity as determined in step (b); and   (d) determining the algorithm by machine-learning from the association of the at least one SNP identified in step (c) with the value indicative for CRH overactivity.   
     
     
         2 . The method according to  claim 1 , wherein the SNP genotyping analysis is performed in a group of at least 10 patients. 
     
     
         3 . The method according to  claim 1 , wherein the SNP genotyping analysis comprises the use of SNP-specific primers, SNP-specific probes, a primer extension reaction, the use of SNP microarrays and/or the use of sequencing methods. 
     
     
         4 . The method according to  claim 1 , wherein the value indicative for CRH activity in each patient is determined by measuring ACTH response to a combined dexamethasone suppression/CRH stimulation test in each patient. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method according to  claim 1 , wherein in step (d) a number N of SNPs identified in step (c) is associated with a value indicative for CRH overactivity, wherein N is sufficient to provide an algorithm having an accuracy of prediction of at least 80% and/or a sensitivity of prediction of at least 70% and/or a specificity of prediction of at least 70% and/or a positive predictive value of prediction of at least 70% and/or a negative predictive value of prediction of at least 70%. 
     
     
         8 . The method according to  claim 7 , wherein N is at least 20. 
     
     
         9 . The method according to  claim 1 , wherein step (c) further comprises identifying at least one SNP associated with a value indicative for normal CRH activity as determined in step (b), and step (d) further comprises machine-learning from the association of the at least one SNP associated with the value indicative for normal CRH activity identified in step (c) with the value indicative for normal CRH activity. 
     
     
         10 . The method according to  claim 1 , wherein the algorithm determined in step (d) associates at least one SNP selected from the group consisting of SNPs described in table 1 and an SNP in strong linkage disequilibrium with an SNP described in table 1 with a value indicative for CRH overactivity or with a value indicative for normal CRH activity. 
     
     
         11 . The method according to  claim 1 , wherein the algorithm determined in step (d) associates the SNPs described in table 1 with a value indicative for CRH overactivity and with a value indicative for normal CRH activity, respectively. 
     
     
         12 . A method for predicting a treatment response to CRHR1 antagonists in patients with depressive symptoms and/or anxiety symptoms, wherein the method comprises the following steps:
 (a) determining in a nucleic acid sample obtained from a patient the presence or absence of at least one single nucleotide polymorphism (SNP) associated with a value indicative for CRH overactivity;   (b) predicting the treatment response to CRHR1 antagonists by linking an algorithm provided by the method of  claim 1  with the presence or absence of the at least one SNP determined in step (a).   
     
     
         13 . The method according to  claim 12 , wherein step (a) comprises determining at least one of the SNPs, which were associated with a value indicative for CRH overactivity when determining the algorithm by machine-learning from this association. 
     
     
         14 . The method according to  claim 12 , wherein step (a) is preceded by a step of obtaining a nucleic acid sample from a patient. 
     
     
         15 . The method according to  claim 12 , wherein in step (a) the presence or absence of a number N of SNPs is determined. 
     
     
         16 . The method according to  claim 15 , wherein N is at least 20. 
     
     
         17 . The method according to  claim 12 , wherein determining in step (a) further comprises determining at least one SNP associated with a value indicative for normal CRH activity. 
     
     
         18 . The method according to  claim 12 , wherein the at least one SNP, determined in step (a) is selected from the group consisting of SNPs described in table 1 and an SNP in strong linkage disequilibrium with an SNP described in table 1. 
     
     
         19 . The method according to  claim 12 , wherein determining in step (a) comprises determining the SNPs described in table 1. 
     
     
         20 . The method according to  claim 12 , wherein the at least one SNP associated with a value indicative for CRH overactivity or with a value indicative for normal CRH activity is determined in step (a) by using SNP-specific primers, SNP-specific probes, a primer extension reaction, SNP microarrays and/or sequencing methods. 
     
     
         21 . A group of biomarkers, comprising:
 SNP rs6437726,   SNP rs1986684,   SNP rs7380830,   SNP rs3903768,   SNP rs7325978,   SNP rs13585,   SNP rs9368373,   SNP rs10935354,   SNP rs8095703,   SNP rs10206851,   SNP rs9542977,   SNP rs4942879,   SNP rs9542954,   SNP rs1593478,   SNP rs9542951,   SNP rs2188534,   SNP rs12524124,   SNP rs4352629,   SNP rs7448716,   SNP rs11873533,   SNP rs10062658,   SNP rs12547917,   SNP rs1038268,   SNP rs2375811,   SNP rs1352671,   SNP rs364331,   SNP rs1924949,   SNP rs11025990,   SNP rs3758562, and   SNP rs10156056.   
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . A method for detecting CRH overactivity in a patient with depressive symptoms and/or anxiety symptoms, comprising determining the status of a biomarker as defined in  claim 21  in a nucleic acid sample isolated from a patient's sample, wherein the presence of indicator nucleotides is indicative for CRH overactivity. 
     
     
         26 . A method for monitoring depression and/or anxiety therapy of a patient with a CRHR1 antagonist comprising the step of determining the status of a biomarker as defined in  claim 21  before and during the therapy. 
     
     
         27 . A method of identifying a patient with depressive symptoms and/or anxiety symptoms as eligible for a therapy with a CRHR1 antagonist, comprising:
 (a) determining in a nucleic acid sample isolated from a patient's sample the status of a biomarker selected from the group consisting of SNP rs6437726, SNP rs1986684, SNP rs7380830, SNP rs3903768, SNP rs7325978, SNP rs13585, SNP rs9368373, SNP rs10935354, SNP rs8095703, SNP rs10206851, SNP rs9542977, SNP rs4942879, SNP rs9542954, SNP rs1593478, SNP rs9542951, SNP rs2188534, SNP rs12524124, SNP rs4352629, SNP rs7448716, SNP rs11873533, SNP rs10062658, SNP rs12547917, SNP rs1038268, SNP rs2375811, SNP rs1352671, SNP rs364331, SNP rs1924949, SNP rs11025990, SNP rs3758562, and SNP rs10156056; and   (b) identifying the patient as eligible for a therapy with a CRHR1 antagonist, where the algorithm provided by the method of  claim 1  predicts that the patient responds to the treatment with CRHR1 antagonists.   
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 27 , further comprising a step of administering a CRHR1 antagonist. 
     
     
         30 . The method of  claim 27 , wherein the CRHR1 antagonist is selected from the group consisting of CP154,526, Antalarmin, CRA 5626, Emicerfont, DMP-696, DMP-904, DMP-695, SC-241, BMS-561388, Pexacerfont, R121919, NBI30545, PD-171729, Verucerfont, NBI34041, NBI35965, SN003, CRA0450, SSR125543A, CP-316,311, CP-376,395, NBI-27914, ONO-2333Ms, NBI-34101, PF-572778, GSK561579 and GSK586529. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . A composition for the analysis of at least one single nucleotide polymorphism (SNP) indicative for the treatment response to CRHR1 antagonists in patients with depressive symptoms and/or anxiety symptoms, comprising a nucleic acid affinity ligand for a biomarker as defined in  claim 21 . 
     
     
         35 . A kit, diagnostic composition or device for the analysis of at least one single nucleotide polymorphism (SNP) indicative for the treatment response to CRHR1 antagonists in patients with depressive symptoms and/or anxiety symptoms, comprising at least one primer and/or probe selective for determining the presence or absence of at least one SNP associated with a value indicative for CRH overactivity. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled)